In the event of a nuclear accident or terrorist bomb, large numbers of casualties will have been exposed to acute high-dose radiation. Those exposed will have compromised immune systems such that the virulence and infectivity of biological agents is dramatically increased. A compromised immune system exacerbates the effects of infectious agents and may preclude use of vaccines. Death can occur within 1-6 weeks following radiation exposure due to overwhelming infection or to massive bleeding. The primary cause of death from radiation injury is infection that is unrestrained due to the failure of the immune system. There is only one intervention that saves a fatally irradiated person - a rescue through stem cell transplantation. The cure rate for this treatment can be high, provided the treatment is delivered within 7-10 days following exposure to radiation. Our goal is to develop very small embryonic like stem cells (VSEL), which are autologous adult pluripotent stem cells, as a countermeasure to radiological and nuclear threat. The VSELs will be used to rescue the immune system of individuals suffering from the delayed effects of acute radiation syndrome (ARS). The cells are autologous and consequently when administered to a patient will not cause rejection or graft- versus host disease, a common cause of failure of allogeneic stem cell therapies. The cells are pluripotent and can be expanded and differentiated to all three germ cell lineages. In particular, VSELs can be differentiated to hemato/lymphopoietic lineage, and can rescue the immune system of mice exposed to lethal radiation. Furthermore, VSELs have been shown to repair damaged tissue in animal models of myocardial infarct and may also be effective in repairing other tissues including retina and pancreas. Consequently, VSELs might be an ideal cell therapy to regenerate the body's immune system and repair other tissues damaged by radiation exposure. Most importantly, VSELs are resistant to lethal irradiation, which destroys hematopoietic stem cells and most other stem cells in the body. Specifically, in mice exposed to lethal radiation, VSELs are alive in bone marrow and proliferate in response to the tissue damage caused by irradiation. Consequently, these cells represent a unique population of autologous PSCs that could be used to treat radiation exposure. Studies proposed in this grant will test whether irradiated VSELs, can rescue the immune system and prolong survival of irradiated mice. If successful, this finding would indicate that VSELs could be isolated from a person exposed to radiation and used to treat that same person. Furthermore, we will test whether human VSELs have the same curative effect as the murine VSELs and are able to reverse the loss of the hemato/lymphopoietic system resulting from whole body irradiation. Importantly, unlike the development of medicinal products which must undergo extensive preclinical testing before human trials, VSELs are autologous and may be more readily available for human testing once preclinical efficacy is established.